Derivatives of a-norprogesterone



United States Patent 3,439,023 DERIVATIVES 0F A-NORPROGESTERONE SeymourD. Levine, Princeton, and Patrick A. Diassi, Wesflield, N.J., assignorsto E. R. Squibb & Sons, Inc., New York, N.Y., a corporation of DelawareNo Drawing. Original application Sept. 28, 1964, Ser. No. 399,838, nowPatent No. 3,381,029, dated Apr. 30, 1968. Divided and this applicationNov. 13, 1967, Ser. No.

Int. 'Cl. C07c 169/36; A61k 17/06 U.S. Cl. 260-488 3 Claims Thisapplication is a division of our application, Ser. No. 399,838, filedSept. 28, 1964.

This invention relates to and has as its object the provision of newphysiologically active steroids, methods for their production and novelintermediates useful in said preparation.

More particularly, this invention relates to the provision of steroidsof the formulae wherein X is halogen (e.g., chloro, bromo, fluoro) and Ris selected from the group consisting of hydrogen and acyl.

The preferred acyl radicals are those of hydrocarbon carboxylic acids ofless than twelve carbon atoms, as exemplified by the lower alkanoicacids (e.g., acetic, propionic butyric and tert-pentanoic acid), thelower alkenoic acids, the monocyclic aryl carboxylic acids (e.g.,benzoic and toluic acids), the monocyclic aryl lower alkanoic acids(e.g., phenacetic and B-phenylpropionic acid), the cycloalkanecanboxylic acids and the cycloalkene carboxylic acids.

The compounds of this invention possess progestational activity and thusmay be employed instead of progesterone, for example, in the treatmentof habitual abortion for which purpose they can be administered in thesame manner as progesterone, for example, the dosage being adjusted forthe relative potency of the particular steroid.

The final products of the instant invention may be prepared by theprocesses of this invention which entails a number of steps beginningwith A-norprogesterone as starting material. The process of the instantinvention may be represented by the following equations wherein R and Xare as hereinbefore defined:

$ COR ll 3,439,023 Patented Apr. 15, 1969 In the first step of theinstant process, A-norprogesterone is enol acylated as by treatment withan acid anhydride, for example, acetic anhydride in the presence of aperacid, for example, perchloric acid, to yield the 17(20)-dehydro-20-acyloxy derivative (Compounds A), which are new compounds of theinstant invention.

Compounds A are then treated with a peracid, for example,m-chloroperbenzoic acid, to yield the l7-substituted A-norprogesterone(Compounds B), which are also new compounds of this invention.

Compounds B are then dehydrogenated as by treatment with adehydrogenating agent, for example, 2,3-dichloro-5,6-dicyanobenzoquinone to yield the A -A-norpregnadiene derivatives(Compounds C), which are new compounds of this invention.

Compounds C are then treated with a peracid, such as m-chloroperbenzoicacid to yield the 6,7-oxido derivatives (Compounds D) which are also newcompounds of the instant invention.

Treatment of Compounds D with 1 mole equivalent of a hydrohalic acid,for example, hydrochloric acid or hydrobromic acid yields the6-halo-7-hydroxy-A -A-norpregnene derivatives (Compounds F), which arealso new compounds of the instant invention.

Alternatively, Compounds D may be treated with an excess of a hydrohalicacid, e.g., hydrobromic or hydrochloric acid at an elevated temperature,to yield the 6- chloro-A -A-norpregnadiene derivatives (Compounds E),which are also new compounds of the instant invention.

The invention may be illustrated by the following examples:

EXAMPLE 1 A A-norpregnadiene-Z-one-ZO-ol acetate (1) An ice-coldsolution of 1.5 ml. of acetic anhydride containing three drops ofperchloric acid is added to a solution of 250 mg. of A-norprogesteronein 8 ml. of carbon tetrachloride and 20 ml. of benzene and left at roomtemperature for one day. The reaction mixture is poured into ice-waterand additional carbon tetrachloride is added. The Organic layer isseparated and washed with a saturated sodium bicarbonate solution and 8%salt solution, dried over sodium sulfate, and evaporated to dryness togive a 280 mg. residue. Plate chromatography of the residue using silicagel as the adsorbent and chloroform containing 1% of methanol as thedeveloping solvent gives a major band at about Rf 0.4, which isdetectable by ultraviolet. Elution with ethyl acetate and evaporation todryness gives a 232 mg. residue. Crystallization of the residue fromether-hexane gives 21 mg. of A -A-norpregnadiene-2-one-20-ol acetatehaving a melting point of 131 132. Recrystallization from isopropylether gives the analytical sample having melting point |13l132; [@1 9 -5(EtOH);

REE; 5.75, 5.92, 6.17 2; R212? 234 my (19,400)

7' Si (CH 9.11 (s, 18-Me); 8.83 (s, l9-Me); 8.21 (s, 2l-Me); 7.90 (s,20-acetate) and 4.27 (s, 3-H).

Analysis.Calcd for C H O (342.46): C, 77.15; H, 8.83. Found: C, 77.20;H, 8.79.

EXAMPLE 2 A -A-norpregnenc-2,20-dione-17a.-ol (III) A mixture of 150 mg.of m-chloroperbenzoic acid and 225 mg. of A A-norpregnadiene-2-one-20-olacetate in 4 ml. of chloroform is stirred at room temperature for twohours. The chloroform solution is washed five times with 5% sodiumhydroxide solution, twice with 8% salt solution, dried over sodiumsulfate and evaporated to dryness to give a gum. The gum is treated witha hot solution of 280 mg. of potassium hydroxide in 5 ml. of methanoland stirred at room temperature for thirty-five minutes and diluted withWater. The precipitate is collected by filtration and washed with waterand driedto give 100 mg. of A -A-norpregnene-2,20-dione-l7a-ol having amelting point of 2l0--2l2. The analytical sample is prepared byrecrystallization from chloroform-ether, M.P. 233-234,

max.

T Si(CH 9.24 (s, 18-Me), 8.82 (s, 19-Me), 7.72 (s,

21-Me); 7.15 (s, 17-hydroxy) and 4.25 (s, 3-H).

Analysis.Calcd for c rr o (316.42): 0, 75.91; H,

8.92. Found: C, 76.09; H, 8.74.

EXAMPLE 3 A A-norpregnene-2,20dione-17a-ol acetate (II) AEtOH max.

A mixture of 61 mg. of A -A-norpregnene-2,20-dione- 17a-ol and 61 mg. ofp-toluenesulfonic acid monohydrate in 0.6 ml. of acetic anhydride and 3ml. of glacial acetic acid is left at room temperature for twenty-twohours, diluted with water and neutralized with potassium carbonate. Thereaction mixture is extracted three times with ether, and the combinedether extracts are washed with 8% salt solution, dried over sodiumsulfate and evaporated to dryness. Crystallization of the residue fromisopropyl ether gives 50 mg. of A -A-norpregnene-2,20 dione-1711-01acetate having a melting point of 182-184. The analytical sample isprepared by recrystallization from isopropyl ether, M.P. 186.5'l87.5,[01.15 47 (EtOH);

A55; 5.78, 5.85, 5.94 (5b.), 6.17;; K5535 23 1 mu (16,300);

1- Si(CH 9.31 (s, 18-Me), 8.81 (s, 19-Me), 7.95 (s,

17-acetate), 7.90 (s, 21-Me) and 4.26 (s, 3 H).

Analysis.Ca1cd for C H O (358.46): C, 73.71; H,

8.44. Found: C, 73.75; H, 8.34.

EXAMPLE 4 A -A-norpregnene-2,20-dione-17a-ol acetate (II) A solution of0.033 ml. of perchloric acid in 3 ml. of acetic anhydride is added to astirred suspension of 4.79 g. of A -A-norpregnene-2,20-dione-l7ot-ol inml. of acetic anhydride. The reaction mixture is stirred at roomtemperature for thirty minutes and then poured into ice water andstirred until the oil which separates initially, solidifies. Theprecipitate is collected by filtration, and dried to give 4.76 g. of A-A-norpregnene-2,20-dione-17a.- ol acetate, M.P. 186187.

EXAMPLE 5 A -A-norpregnadiene-2,20 dione17a-ol acetate (IV) Hydrogenchloride is bubbled into a solution of 1.40 g. of AA-norpregnene-Z,20-dione-17a-ol acetate and 1.0 g. of2,3dichloro-S,6-dicyanobenzoquinone in 30 ml. of dioxane for fiveminutes and the flask is left at room temperature overnight. Thehydroquinone is filtered and the filtrate is evaporated to dryness. Theresidue is treated with chloroform and additional hydroquinone isfiltered. The filtrate is diluted with additional chloroform to a totalvolume of 80 ml. and passed through a 40 g. neutral alumina (Activity I)column. The column is eluted with 420 ml. of chloroform, and the eluateis evaporated to give a 1.42 g. residue, which is refluxed in 30 ml. ofcollidine for seventy-five minutes, cooled to room temperature anddiluted with chloroform. The organic layer is washed with 2 Nhydrochloric solution, saturated sodium bicarbonate solution and 8% saltsolution, dried over sodium sulfate and evaporated to dryness. Platechromatography of the residue using neutral alumina (Activity V) as theadsorbent and chloroform containing 10% hexane as the developing solventgives a major band at about R 0.5, which is detectable by ultraviolet.Elution with ethyl acetate gives a residue which is crystallized fromisopropyl ether to give 764 mg. of AW-A-norpregnadiene-2,20-dione-17a-olacetate having a melting point of -176. The analytical sample isprepared by recrystallization from isopropyl ether, M.P. 178-179, [oflm45 (EtOH);

5.78, 5.87, 6.18 and 6.35,u.; 277 mp (16,300)

'r Si(CH 9.31 (s, 18-Me), 8.88 (s, 1-9-Me), 7.94 (s, 17- acetate), 7.92(s, 21-Me), 4.25 (s, 3-H), 3.83 (d,d,-l cps., 9.5 cps., 6-H), 3.46 (d,d,2-3 cps., 9.5 cps., 7-H).

Analysis.-Calcd for C H O (356.44): C, 74.13; H, 7.92. Found: C, 74.09;H, 7.83.

EXAMPLE 6 A -A-norpregnadiene-2,20-dione-17m-ol (V) EtOH max.

analytical sample is prepared by recrystallization from acetonitrile,MP. 247-248, 0.1 +42 (EtOI-l);

325; 2.91, 5.37, 5.99, 6.20 and 6.35;; x231? 273 mu 22,300)

1- Si(CH 9.18 (s, 18-Me), 8.89 (s, 19-Me), 7.71 (s, 21-Me), 7.12 (s,17-hydroxy), 4.26 (s, 3-H); 3.83 (d,d, 1 cps., 9.5 cps., 6-H), 3.48(d,d, 2 cps., 9.5 cps., 7-H).

Analysis.Calcd for C H O (314.41): C, 76.40; H, 8.34. Found: C, 76.23;H, 8.44.

EXAMPLE 7 611,7 a-oxido-N-A-norpre gnene-2,20-dione-17a-ol acetate (VII)5.78, 5.86, and 6.13 R 235 mp. (11,700)

r Si(CH 9.28 (s, 18-Me), 8.88 (s, 19-Me), 7.94 (s, 17- acetate), 7.88(s, 21-Me), 6.61 (d,d 1 cps, 3.5 cps; 7-H), 6.18 (d, 3.5 cps., 6-1-1),3.78 (s, 3-H).

Analysis.Calcd for 1 1 0 372.44): c, 70.94; H, 7.58. Found: C, 70.97; H,7.57.

EXAMPLE 8 60:,7a-oXido-A -A-n0rpregnene-2,20-Cli0ne-1701-01 (VI)Following the procedure of Example 6, but employing 611,7a-oxido-A -An0rpregnene-2,2.0-dione-17a-ol acetate, there is obtained612,711-oxido-N-A-norpregnene-2,20-dione-17a-ol.

EXAMPLE 9 6B-chloro-A -A-norpregnene-2,20-dione-7a,17ot-diol 17-acetate(X) A solution of 61.5 mg. of 6a,7a-oxido-A-A-norpregnene-2,20-dione-17u-ol acetate in 6 ml. of chloroform istreated with a slight excess of hydrogen chloride in chloroform and leftat room temperature for two and one-half hours. The reaction mixture isdiluted with water and the layers separated. The aqueous phase isextracted with additional chloroform. The chloroform extracts are washedwith an 8% salt solution, dried over sodium sulfate and evaporated todryness. Crystallization of the residue from ethyl acetate-isopropylether gives 50 mg. of 6,8- chloro-A -A-norpregnene-2,20-dione7u,17a-diol17-acetate having a melting point of 236-238. The analytical sample isprepared by recrystallization from ethyl acetateisopropyl ether, MJP.2465-2475", [0:1 :9 76 (EtOI-I);

max.

BtOH 2.86, 5.85, and 6.16,u; 235 (14,800)

-r Si(CH 9.25 (s, 18-Me), 8.58 (s, 19-Me), 7.94 (s, 17- acet-ate), 7.90'(s, 21-Me), 5.93 (m, 7-H), 5.20 (d, 2.5 cps., 6-H), 3.92 (s, 3-H).

Analysis.-Calcd for C H O Cl (408.91): C, 64.60; H, 7.15. Found: C,64.57; H, 7.16.

EXAMPLE 6-chloro-A -A-norpregnadiene-Z,20-dione-17a-o1 acetate (VIII)washed with water, saturated sodium bicarbonate solution and 8% saltsolution, dried over sodium sulfate and evaporated to dryness. Platechromatography of the residue using neutral alumina (Activity V) as theadsorbent and chloroform containing 20% hexane as the developing solventgives a major band at about R 0.8, which is detectable by ultraviolet.Elution with ethyl acetate gives a residue which is crystallized fromisopropyl ether-ethyl acetate to give 177 mg. of 6B-chloro-A-A-norpregnadiene-2,20-dione-17a-ol actate having a melting point of183-194. The analytical sample is prepared by recrystallization fromisopropyl ether-ethyl acetate, M.P. 195.5- 196.5, [M -75 (-EtOH); AZE;5.78 ($11.), 5.87, 6.18 and 6.33% xii? 280 my (19,700) 1- Si(CH 9.26 (s,18-Me), 8.84 (s, 19-Me), 7.95 (s, 17-acetate), 7.91 (s, 21-Me), 3.95'(s, 3-H), 3.78 (d, 2 cps., 7-H) Analysis.Calcd for C H O Cl (390.89):C, 67.66; H, 6.96; Cl, 9.07. Found: C, 67.42; H, 7.00; Cl, 9.09.

EXAMPLE 11 6chloroA -A-norpregnad-iene-2,20-dione-1704-01 Following theprocedure of Example 6, but employing 6chloro-AA-norpregnadiene-2,20-di0ne-17a-ol acetate, there is obtained 6-chloro-A-A-norpregnadiene-2,20- dione-17a-ol.

EXAMPLE l2 613chloroA A-norpregnene-2,20-dione-7a, 17a-dioldiacetateFollowing the procedure of Example 9, but substituting 612,7a-oxido-A-A-norpregnene-2,20-dione-178-01, there is obtained6B-chloroM-A-norpregnene-2,20-dione-7a,17adiol.

EXAMPLE 13 6-bromo-A -A-norpregnadiene-LZO-dione 17 oc-Ol actate where Ris selected from the group consisting of hydrogen and acyl derived froma hydrocarbon carboxylic acid having less than twelve carbon atoms.

2. A -A-norpregnene-2,2O-dione-17ot-ol.

3. A -A-norpregnene-2,20-dione-1706-01 acetate.

References Cited UNITED STATES PATENTS 3,170,919 2/1965 Fried 260-5863,225,064 12/1965 Weisenborn 260-586 3,338,957 8/1967 Weisenborn 260-488LORRAINE A. WEI-NBERGER, Primary Examiner. V. GARNER, AssistantExaminer.

U.S. Cl. X.R.

1. A COMPOUND OF THE FORMULA